Adhesive preparation for external use

ABSTRACT

An external plaster using an aqueous hot melted type adhesive base material stably containing water-soluble drug having good drug releasability, so that bioavailability of the drug is enhanced, is provided. The aqueous hot melted type adhesive base material used in the external plaster comprising as essential components a styrene-isoprene-styrene block copolymer, an adhesive resin, an antioxidant, lanolin, and water.

TECHNICAL FIELD

[0001] The present invention relates to an external plaster using anaqueous hot melted type adhesive base material comprising lanoline andwater as essential components, as well as a process producing thereof.More particularly, the present invention relates to an external plasterusing water containing hot melted type adhesive base material having lowirritation to skin in which crystallization of an active ingredienttherein does not happen and has high bioavailability of the activeingredient.

BACKGROUND ART

[0002] For water containing aqueous external preparations, ointments,lotions, aqueous plasters, and the like have been proposed up to now.Among these external preparations, ointments and lotions have beenconsidered less suitable for administration of an active ingredientcontaining therein continuously and in constant dosages and are alsothought to be inconvenient since they may stick elsewhere other than theintended application site, and may sometimes soil the clothes at thetime of administration.

[0003] Further, an aqueous plaster, though not associated with theseproblems, has a low adhesiveness and thus requires fixing means such asa strip of surgical tape so that it stays on flextion parts such aselbows and knees.

[0004] On the other hand, there has been non-aqueous adhesivespreparation using natural or synthetic rubber as a base material orplaster using adhesive acrylate type resin as base material. These typesof preparations have a strong adhesiveness and are thought to overcomethe drawbacks of aqueous plasters.

[0005] However, it is difficult to dissolve an active ingredient in thenon-aqueous adhesive base material when said active ingredient hardlydissolves in polyols, glycols, and esters, which are commonly used as asolvent for external plasters. Especially, addition of water-solubledrug causes many problems such as appearance of crystalline of the drugsin the base material, low percutaneous absorption of the drugs, and soon due to the low solubility of said drugs

[0006] To solve these problems, for example, there has been proposed touse crotamiton as a solubilizer for the drugs in Japanese PatentLaid-Open Publication No. Hei 4-321624. However, it has been difficultheretofore, even with the help of the solubilizer, to obtain thenon-aqueous adhesive base material that contains drugs in an amountsufficient to allow it to exert desired pharmacological effects.

[0007] By the way, in the case of aqueous plasters containing awater-soluble drug, the drug is solubilized in the adhesive basematerial by ionizing with an organic aqueous amine compound such asdiisopropanol amine, when the drug is an acidic compound. Thoughpossible, adoption of this technique in producing non-aqueous adhesivespreparation containing the water-soluble drug, for example, solventadhesives, which require a drying process, or hot melted type adhesivebase materials, which require exposure to high temperature, may resultin evaporation of moisture and thus crystallization of the drug in theadhesive base.

[0008] A surfactant may also be used as a component of the hot meltedtype adhesive base material in order to facilitate mixing of water. Thisapproach, however, may cause skin irritation and thus is not favorable.

[0009] Aside from the above-described approaches, a water-absorbable orwater-soluble high molecular compound is thought to enable the adhesivematerial to absorb water. One disadvantage of this approach is thatmoisture evaporates when the temperature is raised to melt thesuccessive adhesive in continuous production. As a result, the highmolecular compound crystallizes and forms unwanted particles in theadhesive base. Moreover, water is surrounded by the high molecularcompound which is presented in the adhesive base material, and thisprevents diffusion of the drug, i.e., the active ingredient, in theadhesive preparation, and as a result, the efficiency of the drugutilization is lowered.

[0010] Accordingly, it is an objective of the present invention toprovide external plasters using an aqueous hot melted type adhesive basematerial which stably contains the active ingredient and exhibits a goodreleasability of the drug from the adhesive base material, therebyenhancing bioavailability of the drug based on the percutaneousabsorption.

SUMMARY OF THE INVENTION

[0011] The present invention has been devised to overcome theabove-described problems and provides in one aspect an external plasterusing an aqueous hot melted type adhesive base material comprises asessential components a styrene-isoprene-styrene block copolymer, anadhesive resin, an antioxidant, lanolin, and water.

[0012] More specifically, the present invention provides an externalplaster using above-mentioned aqueous adhesive base material, wherein anactive ingredient to be percutaneously absorbed is contained in saidadhesive base material.

[0013] In one preferred embodiment of the present invention, theexternal plaster contains water in an amount of 0.1 to 30%.

[0014] In summary, what is characteristic of the present inventionresides containing an water-soluble drug in the hot melted type adhesivebase material that contains a styrene-isoprene-styrene block copolymer,an adhesive resin, an antioxidant, lanolin and water as essentialcomponents. The plaster using said aqueous hot melted type adhesive basematerial has enhanced drug stability as well as enhanced drugreleasability over time and thus overcomes the aforementioned drawbacksof the conventional art.

BEST MODE FOR CARRYING OUT THE INVENTION

[0015] An external plaster in accordance with the present invention willnow be described in detail with the emphasis on the types and theamounts of the components contained.

[0016] Lanolin for use in the plaster of the present invention is alsocalled “wool fat” and is purified and collected when secretions of sheepare washed off of wool. Lanolin is a cholesterin fat that does not loseits ointment-like viscosity even when added with 2 to 3 times as muchwater and is readily soluble in ether, chloroform, petroleum, benzine,or the like.

[0017] What is characteristic of the plaster of the present inventionresides in the use of lanolin as a component of the adhesive basematerial for the plaster.

[0018] Styrene-isoprene-styrene block copolymer (hereinafter referredsimply as to “SIS”) for use in the plaster of the present invention issynthetic rubber to form the basic component of the adhesive basematerial and has ratio of styrene/rubber as 14/86. While adhesive basematerials containing SIS are normally produced by melting attemperatures of 120 to 160° C., it is essential to design the productionprocess of the aqueous hot melted type adhesive base material of thepresent invention so that the components are kneaded and mixed at about90° C. in order to permit mixing of water.

[0019] It is thus preferred that the amount of SIS to be used is from 10to 25% (as measured in % by weight with respect to the total weight ofthe adhesive preparation. All of the numbers expressed in percentagesappear in the following description are calculated in the same manner.),more preferably from 15 to 25%. If the amount is less than 10%, thecohesion of the adhesive material is lost and it tends to remain on thesurface to which it is applied after the plaster has been removed. Incomparison, if the amount exceeds 25%, the adhesive base materialbecomes hard, making kneading and mixing of the adhesive base materialdifficult. As a result, the adhesion of the base material is reduced.

[0020] Adhesion resin for use in the plaster of the present inventionmay be any of the following resin materials such as aromatic resins,aliphatic resins, alicyclic petroleum resins, rosin resins, rosin esterresins and terpene resins.

[0021] The amount of the adhesive resin to be used is preferably from 15to 35%, and more preferably from 20 to 30%. If the amount is less than15%, then the adhesive base material can hardly exhibit the adhesion,and the cohesion of the adhesive base material is reduced. As a result,the base material tends to remain on the surface to which it is appliedafter the plaster has been removed. In comparison, if the amount exceeds35%, the adhesive base material becomes hard, making kneading and mixingof the adhesive difficult. As a result, the adhesiveness of the basematerial is reduced.

[0022] Antioxidant for use in the plaster of the present invention iscontained for the purpose of preventing the adhesive base material fromundergoing deterioration due to oxidation during mixing and storage ofthe adhesive base material. Examples of the antioxidant includedibutylhydroxytoluene, pentaerythrityl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)]propionate, and tocopherol acetate.Preferably, these antioxidants are added in an amount of 0.1 to 2%.

[0023] Lanoline is used to serve not only to retain moisture in theadhesive base material but also as a softener of the adhesive basematerial. The amount of lanolin to be used is determined based on thebalance between the amount of water and the amounts of other oils andfats and the softeners such as liquid rubbers. Preferably, the amount oflanolin is from 5 to 40% and more preferably from 10 to 30%. Lanolincontained in an amount less than 5% is insufficient for stable retentionof water, whereas when contained in an amount greater than 40%, it makesthe adhesive base material unfavorably sticky.

[0024] Water is contained for the purposes of dissolving a drug, i.e.,an active ingredient and providing the base material with a sense of“cooling effect”. The amount of water is determined based on the balancebetween the amount of the active ingredient and the amount of lanolinand is preferably from 0.1 to 30% and more preferably from 0.3 to 20%.If the amount of water is less than 0.1%, it becomes difficult not onlyto dissolve the drug in the base material but also to provide the“cooling effect” to the plaster. In comparison, the adhesive preparationcan hardly have required properties if the amount of water exceeds 30%.

[0025] The drugs to be used in the external plaster of the presentinvention may be percutaneously absorbable and water-soluble drugs, andnot limited those drugs. Examples include analgesic andanti-inflammatory, depressor, diuretic, anti-allergic, anti-asthmatic,coronaria vasodilator, bronchodilator, â-blocker and the like.

[0026] Examples of analgesic and anti-inflammatory drugs may includemethyl salicylate, glycol salicylate, indometacin, ketoprofen,flurbiprofen, ibuprofen, diclofenac sodium, mefenamic acid, flufenamicacid, ibufenac, acrofenac, loxoprofen, piroxicam, naproxen, oxaprozin,silindac, felbinac (4-biphenyly acetic acid; hereinafter referred simplyas to “BPAA”), and the like.

[0027] Examples of depressor may include clonidine, clonidinehydrochloride, atenolol, propranolol, propranolol hydrochloride,nicardipine hydrochloride, bupranolol, metoprolol tartrate, captopril,indenolol, nifedipine, and the like.

[0028] Further, examples of diuletic may include acetazolamide,potassium canrenoate, chlortalidone, spironolactone,trichlor-methiazide, flusemide, hydrochlorothiazide, hydroflumethiazide,and the like.

[0029] Examples of anti-allergic may include diphenhydraminehydrochloride, cyproheptadine hydrochloride, homochlorcyclizinehydrochloride, clemastine fumarate, chlorpheniramine maleate,mequitazine, and the like.

[0030] Examples of anti-asthmatic (antitussive) may include ephedrinehydrochloride, methylephedrine hydrochloride, pentoxyverine citrate,dextromethorphan hydrobromide, terbutaline sulfate, isoprenalinehydrochloride, and the like.

[0031] Examples of coronaria vasodilator may include nitroglycerin,nitroglycol, isosorbide nitrate, dipyridamole, molisidomine, and thelike, and examples of bronchodilator may include trimetrquinolhydrochloride, procaterol hydrochloride, mabuterol hydrochloride,salbutamol sulfate, theophylline, tulobuterol and the like.

[0032] The plaster of the present invention may optionally contain apharmaceutically acceptable absorption enhancer, refrigerant,preservative, bactericide, pigment and other pharmaceutically acceptableagents as desired.

[0033] Using the above-described adhesive components, the externalplaster of the present invention can be manufactured, for example,through the following process.

[0034] For example, SIS, the adhesive resin, the antioxidant, lanolin,and the softener are melted, mixed, and kneaded in a kneader heated toabout 150° C. to obtain the adhesive base material, which is then cooledto 90° C. by air or water.

[0035] Subsequently, warm water, together with a drug solution (aqueous)to serve as the active ingredient solution, is added gradually to theadhesive base material under stirring. The resulting adhesive basematerial is spread on the liner to a predetermined thickness, and then,laminated with the backing. Then, the backing thus obtained is cut intodesired size to produce the plaster of the present invention.

[0036] Alternatively, the adhesive base material may be prepared in aseparate container and is stored into block forms. A required amount ofthe block forms is then melted at about 90° C. and mixed with water andthe active ingredient solution.

[0037] If the temperature of the adhesive base material exceeds 100° C.during addition of the aqueous solution of the active ingredient andwater, water is brought to boiling and evaporates, and as a result, theamount of water in the plaster is significantly reduced. In comparison,if the temperature is lower than 80° C., the adhesive base materialbecomes so viscous that it is difficult to stir the mixture during theaddition of the aqueous solution of the active ingredient. This preventsuniform dispersion of the active ingredient.

EXAMPLES

[0038] The present invention will be further illustrated by thefollowing examples. It is to be understood that the present invention isnot limited to these examples. Details may be deleted, added, orsubstituted as it is deemed to be appropriate, so long as thepharmacological activities of the plaster of the present invention isnot changed. Such changes are also covered within the technical scope ofthe present invention. Thus the temperature at the adding and mixing ofthe aqueous solution must be 80 to 100° C.

EXAMPLES 1 to 5

[0039] BPAA, an analgesic and anti-inflammatory drug was used for theactive ingredient of these examples. Adhesive base materials withformulations shown in Tables 1 below were prepared.

[0040] A sheet of polyester film treated with silicone was used to serveas a liner, and a piece of fabric made from polyester fiber was used toserve as a backing for each adhesive base material. The amount of eachadhesive base material coated was 100 g/m². TABLE 1 Formulations ofadhesive base material of example 1 to 5 Materials Ex. 1 Ex. 2 Ex. 3 Ex.4 Ex. 5 SIS 14.0  18.0  16.0  17.0  16.0  Saturated alicyclic 25.0 — — —— petroleum resin Rosin ester resin — 22.0  — — — Terpene resin — —24.0  25.0  24.0  Polybutene — — 7.0 19.0  6.0 Liquid paraffin 13.0  6.017.0  8.0 — Polyethyleneglycol-400 — — 10.0  5.0 — Dibutylhydroxytoluene1.0 1.0 1.0 1.0 1.0 Lanolin 24.0  25.0  10.0  10.0  25.0  Purified water9.0 9.0 1.0 1.0 9.0 Purified water 1.0 1.0 1.0 1.0 1.0 (solvent for theBPAA) Diisopropanolamine 5.0 5.0 5.0 5.0 10.0  Crotamiton 2.5 2.5 2.52.5 2.5 BPAA 5.0 5.0 5.0 5.0 5.0 1-menthol 0.5 0.5 0.5 0.5 0.5 Isopropylmyristate — 5.0 — — —

COMPARATIVE EXAMPLES 1 to 4

[0041] As Comparative Examples, external plaster using water-free hotmelted type adhesives base material and commercially available acrylicacid ester adhesives were prepared. Formulation for each ComparativeExample is shown in Table 2 below. TABLE 2 Formulations of adhesive basematerial for Comparative Examples (Comp. 1 to 4) Materials Comp. 1 Comp.2 Comp. 3 Comp. 4 SIS 18.0  20.0  — — Terpene resin 29.0  31.0  — —Polybutene 15.0  15.0  — — Liquid paraffin 9.0 15.0  — —Polyethyleneglycol-400 5.0 5.0 5.0 5.0 Dibutylhydroxytoluene 1.0 1.0 — —Acrylic adhesive A *¹ — — 72.0  — Acrylic adhesive B *² — — — 72.0 Lanolin 10.0  10.0  10.0  Diisopropanolamine 5.0 5.0 5.0 5.0 Crotamiton2.5 2.5 2.5 2.5 BPAA 5.0 5.0 5.0 5.0 1-menthol 0.5 0.5 0.5 0.5

[0042] Test Example 1: Drug Permeability Test

[0043] Using a commercially available aqueous BPAA plaster (cataplasm)as a control, the above-prepared plasters of Examples and ComparativeExamples were tested for the ability to permeate the drug component inthe in vitro skin permeability tests.

[0044] Methods:

[0045] Using a scalpel and scissors, a piece of abdominal skin was cutfrom a hairless rat and was mounted on a vertically placed Franzdiffusion cell with the receptor compartment filled with saline. Warmwater with a temperature of about 35° C. was circulated through thejacket of the cell.

[0046] The above-prepared plasters were each applied to the skin ofhairless rat, and the receptor solution was sampled over time for eachplaster. The amount of the drug permeated in 24 hours was determined byHPLC.

[0047] Results:

[0048] The results of the tests are shown in Table 3. For thecommercially available aqueous BPAA plaster (cataplasm) serving as thecontrol, the amount of the permeated drug was 66.0 ig/cm². TABLE 3Results of rat skin permeability test Plaster No. Ex. 1 Ex. 2 Ex. 3 Ex.4 Ex. 5 Amount permeated ig/cm² 58.2 174.6 62.4 81.5 65.8 Plaster NoComp. 1 Comp. 2 Comp. 3 Comp. 4 Amount permeated 29.8 21.5 43.7 31.6ig/cm²

[0049] As can be seen from the results of Table 3 above, the plaster ofExamples of the present invention each exhibited higher skinpermeability than the plaster of Comparative Examples. This indicatesthat the plaster of the present invention has an improved releasabilityof the drug.

[0050] Test Example 2: Stability Test

[0051] The above-prepared plasters of Examples and Comparative Exampleswere each placed in a polyethylene-aluminum bag, were stored for 6months at 40° C., and were then examined for the presence of crystaldeposition.

[0052] No crystal deposition was observed on the plasters of Examples,whereas crystals formed on the plasters of Comparative Examples as earlyas after 1 month, causing the plasters to remain stuck to the liner andsignificantly reducing the adhesion. No decrease was observed in theamount of the active ingredient (BPAA) in any of the preparations.

[0053] The presence or the absence of crystal deposition on the plastersobserved after the storage period was shown in Tables 4 and 5, with theresults of the adhesive strength of the plasters.

[0054] The adhesive strength (unit=g/25 mm) was measured by peeling theplaster from a Bakelite plate at 180° angles. TABLE 4 Results ofstability test (Examples 1 to 5) Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 InitialCrystal None None None None None (after production) Adhesive 780 890 540690 750 strength 40° C. Crystal None None None None None 1 monthAdhesive 750 870 610 710 770 strength 40° C. Crystal None None None NoneNone 3 months Adhesive 760 890 590 680 730 strength 40° C. Crystal NoneNone None None None 6 months Adhesive 740 790 620 690 750 strength

[0055] TABLE 5 Results of stability test (Comparative Examples 1 to 4)Comp. 1 Comp. 2 Comp. 3 Comp. 4 Initial Crystal None None None None(after Adhesive 2340 1780  2540  1520  production) strength 40° C.Crystal formed formed formed Formed 1 month Adhesive 1580 320 410 280strength 40° C. Crystal formed formed formed Formed 3 months Adhesive1460 380 340 250 strength 40° C. Crystal formed formed formed Formed 6months Adhesive 1390 350 390 280 strength

EXAMPLES 6 and 7 External Plaster Containing Salbutamol Sulfate andPropranolol Hydrochloride

[0056] Salbutamol sulfate as bronchodilator, and proprnololhydrochloride as a-broker for treatment of angina were used for theactive ingredient of these examples. Adhesive base materials withformulations shown in Tables 6 below were prepared.

[0057] A sheet of polyester film treated with silicone was used to serveas a liner, and a piece of fabric made from polyester fiber was used toserve as a backing for each adhesive base material. The amount of eachadhesive base material coated was 100 g/m^(2.) TABLE 6 Formulations ofadhesive base material of examples 6 and 7 Materials Ex. 1 Ex. 2 SIS22.0  20.0  Saturated alicyclic 25.0  25.0  petroleum resin Polybutene8.0 7.0 Lanolin 20.0  250   Polyethyleneglycol-400 3.0 3.0 Crotamiton2.0 2.0 Dibutylhydroxytoluene 1.0 1.0 Diethyl sebacate 3.0 — Oleic acid— 1.0 Purified water 10.0  10.0  Salbutamol sulfate (Active ingredient)6.0 — propranolol hydrochloride — 6.0 (Active ingredient)

[0058] Test Example 3: Drug Permeability Test

[0059] The above-prepared plasters of Examples 6 and 7 were tested forthe ability to permeate the drug component in the in vitro skinpermeability tests.

[0060] Methods:

[0061] Using a scalpel and scissors, a piece of abdominal skin was cutfrom a hairless rat (6 rats for each groups) and was mounted on avertically placed Franz diffusion cell with the receptor compartmentfilled with saline. Warm water with a temperature of about 35° C. wascirculated through the jacket of the cell.

[0062] The above-prepared plasters were each applied to the skin ofhairless rat, and the receptor solution was sampled over time for eachplaster. The amount of the drug permeated at 2, 4, 6, 8 and 24 hoursafter administration was determined by HPLC.

[0063] Results:

[0064] The results of the tests are shown in Table 7. TABLE 7 Results ofrat skin permeability test Rat skin permeability test for plastercontaining salbutamol sulfate (Example 6) Drug amount permeated at eachtimes (ig/cm²) Time 0 2 4 6 8 24 Amount 0 2.17 3.18 5.56 7.29 20.9 Ratskin permeability test for plaster containing propranolol hydrochloride(Example 7) Drug amount permeated at each times (ig/cm²) Time 0 2 4 6 824 Amount 0 2.41 9.84 19.27 25.82 59.76

[0065] As can be seen from the results of Table 7 above, the plaster ofExamples of the present invention each exhibited higher skinpermeability and good releasability of the drug.

[0066] Industrial Applicability

[0067] As mentioned above, the external plaster of the presentinvention, which is using an aqueous hot melted type adhesive basematerial comprising as essential components a styrene-isoprene-styreneblock copolymer, an adhesive resin, an antioxidant, lanolin, and water,is advantageous in that it exhibits a good drug stability as well as agood drug releasability over time and the adhesion of the plaster is notdecreased over time.

1. An external plaster using an aqueous hot melted type adhesive basematerial comprises as essential components a styrene-isoprene-styreneblock copolymer, an adhesive resin, an antioxidant, lanolin, and water.2. The external plaster according to claim 1, wherein water amount is ina range of 0.1 to 30%.
 3. The external plaster according to claims 1 or2, wherein an active ingredient to be percutaneously absorbed iscontained in the aqueous hot melted type adhesive base material.
 4. Aprocess for producing an aqueous hot melted type adhesive base material,which comprises melting and kneading a styrene-isoprene-styrene blockcopolymer, an adhesive resin, an antioxidant, lanolin, and water asessential components at a temperature of 80 to 100° C.